Bottom Line:
Indeed, in addition to tauopathies, which comprise approximately 30 diseases characterized by neuronal aggregation of hyperphosphorylated Tau in brain neurons, this protein has also been associated with various other pathologies such as cancer, inclusion body myositis, and microdeletion/microduplication syndromes, suggesting its possible function in peripheral tissues.Here, we aim to review current knowledge regarding the regulation of human MAPT gene expression at the DNA and RNA levels to provide a better understanding of its possible deregulation.Several aspects, including repeated motifs, CpG island/methylation, and haplotypes at the DNA level, as well as the key regions involved in mRNA expression and stability and the splicing patterns of different mRNA isoforms at the RNA level, will be discussed.

ABSTRACTThe number of known pathologies involving deregulated Tau expression/metabolism is increasing. Indeed, in addition to tauopathies, which comprise approximately 30 diseases characterized by neuronal aggregation of hyperphosphorylated Tau in brain neurons, this protein has also been associated with various other pathologies such as cancer, inclusion body myositis, and microdeletion/microduplication syndromes, suggesting its possible function in peripheral tissues. In addition to Tau aggregation, Tau deregulation can occur at the expression and/or splicing levels, as has been clearly demonstrated in some of these pathologies. Here, we aim to review current knowledge regarding the regulation of human MAPT gene expression at the DNA and RNA levels to provide a better understanding of its possible deregulation. Several aspects, including repeated motifs, CpG island/methylation, and haplotypes at the DNA level, as well as the key regions involved in mRNA expression and stability and the splicing patterns of different mRNA isoforms at the RNA level, will be discussed.

Mentions:
SSRs can be found throughout the MAPT gene using the Tandem Repeats Finder program (TRF/UCSC) [70]. Interestingly, the first genetic marker identified as over-represented in PSP patients was a dinucleotide repeat (11xTG, named TG11) downstream of exon 9 ([71, 72], reviewed in [60]). Some of these repeats are clearly distinguishable based on the following features: (i) their repeat length (4 sequences are longer than 20 nt, and the longest sequence is 58 nt); (ii) their localization throughout the gene (shorter sequences of less than 20 nt are located before exon E4, whereas the longest sequence, which is more than 20 nt long, is located after E4); (iii) their proximity to alternative exons; and (iv) the repeat lengths of certain imperfect repeats, such as those of the dinucleotides TA or GT in intron 0 (TA356, GT187) (Fig. 1). A 58-nt motif (SSR58) that is repeated twice is located immediately upstream (precisely 10 nt) of the alternatively spliced E10 [73, 74]. Interestingly, the copy number of this long repeat seems to influence the splicing pattern of this exon [73]. Although no functional role has been demonstrated, notably, a dinucleotide GT repeat (x22: GT22) has been identified immediately downstream of E0 (precisely 362 nt from E0) in the human gene, as first reported by Andreadis et al. [75]. Compared with the mouse sequence, half of this human TG repeat corresponds with an insertion in a sequence that is well-conserved (76 % homology) between human and mouse E0. However, a similar 23-repeat TG sequence also exists in intron 0 of mouse MAPT, but it is located 7301 nt downstream instead of 362 nt downstream of E0 in a non-homologous region of the human gene. We also observed 4 different short regions containing CATC or CCAT repeats located immediately downstream (from 46 to 1200 nt) of the internal exon E1A, between E1 and E2 in the only MAPT transcript that is potentially subjected to nonsense-mediated decay (NMD) (MAPT-011 ENST00000571311) (Fig. 1, Fig. 4b).Fig. 1

Mentions:
SSRs can be found throughout the MAPT gene using the Tandem Repeats Finder program (TRF/UCSC) [70]. Interestingly, the first genetic marker identified as over-represented in PSP patients was a dinucleotide repeat (11xTG, named TG11) downstream of exon 9 ([71, 72], reviewed in [60]). Some of these repeats are clearly distinguishable based on the following features: (i) their repeat length (4 sequences are longer than 20 nt, and the longest sequence is 58 nt); (ii) their localization throughout the gene (shorter sequences of less than 20 nt are located before exon E4, whereas the longest sequence, which is more than 20 nt long, is located after E4); (iii) their proximity to alternative exons; and (iv) the repeat lengths of certain imperfect repeats, such as those of the dinucleotides TA or GT in intron 0 (TA356, GT187) (Fig. 1). A 58-nt motif (SSR58) that is repeated twice is located immediately upstream (precisely 10 nt) of the alternatively spliced E10 [73, 74]. Interestingly, the copy number of this long repeat seems to influence the splicing pattern of this exon [73]. Although no functional role has been demonstrated, notably, a dinucleotide GT repeat (x22: GT22) has been identified immediately downstream of E0 (precisely 362 nt from E0) in the human gene, as first reported by Andreadis et al. [75]. Compared with the mouse sequence, half of this human TG repeat corresponds with an insertion in a sequence that is well-conserved (76 % homology) between human and mouse E0. However, a similar 23-repeat TG sequence also exists in intron 0 of mouse MAPT, but it is located 7301 nt downstream instead of 362 nt downstream of E0 in a non-homologous region of the human gene. We also observed 4 different short regions containing CATC or CCAT repeats located immediately downstream (from 46 to 1200 nt) of the internal exon E1A, between E1 and E2 in the only MAPT transcript that is potentially subjected to nonsense-mediated decay (NMD) (MAPT-011 ENST00000571311) (Fig. 1, Fig. 4b).Fig. 1

Bottom Line:
Indeed, in addition to tauopathies, which comprise approximately 30 diseases characterized by neuronal aggregation of hyperphosphorylated Tau in brain neurons, this protein has also been associated with various other pathologies such as cancer, inclusion body myositis, and microdeletion/microduplication syndromes, suggesting its possible function in peripheral tissues.Here, we aim to review current knowledge regarding the regulation of human MAPT gene expression at the DNA and RNA levels to provide a better understanding of its possible deregulation.Several aspects, including repeated motifs, CpG island/methylation, and haplotypes at the DNA level, as well as the key regions involved in mRNA expression and stability and the splicing patterns of different mRNA isoforms at the RNA level, will be discussed.

ABSTRACTThe number of known pathologies involving deregulated Tau expression/metabolism is increasing. Indeed, in addition to tauopathies, which comprise approximately 30 diseases characterized by neuronal aggregation of hyperphosphorylated Tau in brain neurons, this protein has also been associated with various other pathologies such as cancer, inclusion body myositis, and microdeletion/microduplication syndromes, suggesting its possible function in peripheral tissues. In addition to Tau aggregation, Tau deregulation can occur at the expression and/or splicing levels, as has been clearly demonstrated in some of these pathologies. Here, we aim to review current knowledge regarding the regulation of human MAPT gene expression at the DNA and RNA levels to provide a better understanding of its possible deregulation. Several aspects, including repeated motifs, CpG island/methylation, and haplotypes at the DNA level, as well as the key regions involved in mRNA expression and stability and the splicing patterns of different mRNA isoforms at the RNA level, will be discussed.